Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with appreciable morbidity and mortality. Current treatment comprises non-specific immunosuppression with many serious side-effects. Furthermore, response to therapy is often incomplete. More specific, and less toxic therapies are thus required. Interferon regulatory factor 5 (IRFS) polymorphisms are strongly associated in human genetic studies with an increased risk of developing SLE although the biological role of IRFS in lupus pathogenesis, if any, is not known. We have found that IRFS is absolutely required for disease development in a mouse model of SLE. In addition, a critical level of IRFS is required as IRFS heterozygous mice develop minimal disease manifestations. This suggests that IRFS might be a key therapeutic target in SLE. The application's objectives are to obtain a detailed understanding of the mechanisms whereby IRFS contributes to disease pathogenesis in SLE. The goal of specific aim 1 is to determine the role of IRFS in lupus-relevant immune responses by comparing the functional effects of homozygous and heterozygous IRFS deficiency on the response of dendritic cells and B cells to TLR stimuli including DNA- and RNA-containing immune complexes. Specific aim 2a will determine the generalizability of the IRFS role in SLE by evaluating the effect of IRFS-deficiency in additional lupus models. Specific aim 2b will determine to what extent the beneficial effect of IRFS-deficiency in lupus is TLR7- and/or TLR9-dependent or independent. Specific aim 2c will determine whether IRFS overexpression is able to induce disease in wildtype or autoimmune-prone mice. Specific aim 3 will determine which IRFS-expressing cells are required for disease pathogenesis by using bone-marrow chimeras, and by deleting IRFS in specific cell types using a Cre-loxP approach with cell- specific Cre. Specific aim 4 will determine whether deleting IRFS (in all cell types) after disease is established can reverse disease or prevent disease progression. This will be done also using a Cre-loxP approach but using an inducible Cre. It is anticipated that these studies will enhance the understanding of the role of IRFS in SLE pathogenesis and contribute to the development of new effective, safer and more specific therapies. RELEVANCE (See instructions): Genetic abnormalities in a protein called interferon regulatory factor S (IRFS) are found in many patients with the autoimmune disease systemic lupus erythematosus (SLE). We have found in an animal model of SLE that deficiency of IRFS prevents the development of disease. This suggests that IRFS might be a key therapeutic target in SLE